New gene target offers hope for fatal infant cardiomyopathy

Researchers from the Keck School of Medicine of USC have made an important advance toward understanding-and potentially treating-a rare cardiomyopathy (heart muscle disease) that is present from birth. The condition, known as AARS2-related cardiomyopathy, is caused by inherited mutations in the alanyl-transfer RNA (tRNA) synthetase 2 (AARS2) gene and is often fatal within the first year of life. Currently, no treatment or cure exists.

Past efforts to treat AARS2-related cardiomyopathy have focused on repairing mutations in the AARS2 gene. But a new study reveals that another gene, PCBP1, may offer an alternative way to intervene.

Although PCBP1 is not the gene that causes the disease, the researchers found that it helps control how the non-mutated AARS2 gene functions in heart cells, making it a possible new point of intervention to prevent damage to the heart. In mice and lab-grown human heart cells, they found that switching off PCBP1 reproduces key features of the disease. They also uncovered how the damage happens, including by disrupting mitochondria, which produce the energy that fuels cells.

The findings suggest that targeting PCBP1 could help restore healthier AARS2 function in heart cells. The research was funded in part by the National Institutes of Health and just published in the journal Nature Cardiovascular Research.

This is the first time PCBP1 has been linked to this disease. We were able to trace its effects on AARS2 down to the molecular level, which gives us strong evidence that PCBP1 can influence how this disease develops." 

Yao Wei Lu, PhD, study's lead and corresponding author, assistant professor of medicine and member of the Hastings Center for Pulmonary Research at the Keck School of Medicine

In addition to opening potential new paths for treating AARS2-related cardiomyopathy, the findings could have broader relevance. Many other rare diseases affecting the heart, brain and other organs also involve problems with mitochondria. By showing how these breakdowns happen at the genetic and cellular level, the study may point to new treatment strategies for a wide range of disorders.

Linking AARS2 and PCBP1

PCBP1, short for poly(rC)-binding protein 1, codes for a protein of the same name. When working properly, this protein helps process genetic messages that tell cells how to function. When PCBP1 is missing, that process can go awry.

In mice, Lu and his colleagues used a genetic approach that allowed them to delete PCBP1, but only in heart muscle cells. This helped them isolate the gene's role in heart development and disease.

The researchers then identified a chain of events linking PCBP1, AARS2 and heart muscle disease. When PCBP1 is missing, the genetic message from AARS2 is processed incorrectly in a way that looks very similar to the AARS2-related cardiomyopathy seen in human patients. The result is that mitochondrial activity is disrupted, reducing the cell's energy supply. In an attempt to compensate, heart cells switch on stress signals that cause further damage.

The researchers also used human induced pluripotent stem cells (iPSCs), reprogrammed adult cells, to create heart muscle cells in the lab. When they switched off PCBP1, they observed similar effects in mitochondria, suggesting the same process occurs in human cells.

Broader treatment potential

In addition to revealing key details about the mechanism behind AARS2-related cardiomyopathy, the study produced a mouse model of the condition that should make it easier to study. Lu and his team are now exploring potential treatments in both mice and iPSCs. 

They are also investigating whether a similar approach could help treat other diseases where mitochondrial problems damage the heart, brain, lungs or kidneys.

"We think what we found in the heart can apply to many of these organs, because the root cause-mitochondrial dysfunction-is the same," Lu said.

Lu's collaborators include his former mentors Da-Zhi Wang, PhD, of the University of South Florida, and Hong Chen, PhD, of Boston Children's Hospital and Harvard Medical School; George Porter, MD, PhD, from the University of Rochester Medical Center, a pediatric cardiologist who led analyses of mitochondrial function; Frank Conlon, PhD, from the University of North Carolina at Chapel Hill, who led the proteomics analysis; and Jessie Huang, PhD, of the Keck School of Medicine of USC, who helped build the iPSC-based model.